Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions

Abstract

Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos+ brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage.

Motor learning selectively strengthens cortical and striatal synapses of motor engram neurons

“…Preliminary chemogenetic silencing experiments did not significantly affect the performance of trained mice in our hands. Given that memory engrams are likely distributed across many brain regions (Vetere et al, 2017;Josselyn and Tonegawa, 2020;Roy et al, 2022) and the previous finding that ablating the entire M1 does not prevent mice from performing learned motor sequences (Kawai et al, 2015), inhibiting engram neurons only in the motor cortex might not be sufficient to disrupt learned behaviors.…”

Remote contextual fear retrieval engages activity from salience network regions in rats

“…Moreover, it is unclear when memory retrieval would become independent of hippocampal subregions and more dependent on neocortical ones ( Frankland and Bontempi, 2005 ). Recent evidence demonstrates that a brain-wide engram circuit is allocated after memory acquisition ( Rao-Ruiz et al, 2021 ; Roy et al, 2022 ). Previous studies showed that for the CFC task there is engram allocation in the hippocampus, mPFC (including the prelimbic cortex and the ACC), aRSC and amygdala ( Matos et al, 2019 ; Ohkawa et al, 2015 ).…”

“…Parallel to the research into systems consolidation and time-dependent fear generalization, other studies also suggest that recognition, spatial or emotional memory engram cells are allocated during acquisition in several brain regions other than the hippocampus ( Roy et al, 2016 , 2022 ). Some of these regions are the amygdala ( Redondo et al, 2014 ), the anterior insular cortex (aIC) ( Sano et al, 2014 ) and the mPFC, especially the prelimbic cortex (PL) ( Zhang et al, 2011 ).…”

Remote contextual fear retrieval engages activity from salience network regions in rats

“…Parallel to the research into systems consolidation and time-dependent fear generalization, other studies also suggest that recognition, spatial or emotional memory engram cells are allocated during acquisition in several brain regions other than the hippocampus (Roy et al, 2022, 2016). Some of these regions are the amygdala (Redondo et al, 2014), the anterior insular cortex (aIC) (Sano et al, 2014) and the mPFC, especially the prelimbic cortex (PL) (Zhang et al, 2011).…”